Rapid Review·General Pathology
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INFLAMMATION
T2High yieldChemical Mediators of Inflammation (Arachidonic Acid Pathway)
P209
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Focus on
One membrane lipid feeds two enzymatic arms, and every anti-inflammatory drug is defined by where on that fork it cuts.
Key takeaways
The trunk: phospholipase A2
- Inhibited by corticosteroids, which act at the very top and therefore shut off BOTH downstream arms.
- This is the single most tested branch point on the page.
Arm 1: cyclooxygenase
- Aspirin acetylates COX IRREVERSIBLY, so platelet inhibition lasts the ~7 to 10 day life of the platelet, which cannot make new enzyme. Other NSAIDs bind reversibly.
- PGE2 and PGI2: vasodilation, ↑ vascular permeability, pain, fever.
- PGE2 also protects the gastric mucosa (which is why NSAIDs cause ulcers, and why misoprostol, a PGE1 analog, prevents them) and maintains a patent ductus arteriosus (alprostadil keeps it open, indomethacin closes it).
- Thromboxane A2, made by platelets: vasoconstriction plus platelet aggregation.
- Prostacyclin (PGI2), made by endothelium: vasodilation plus inhibition of platelet aggregation. It is the exact counterweight to TXA2, and epoprostenol exploits it in pulmonary hypertension.
Arm 2: lipoxygenase
- LTB4: potent neutrophil chemoattractant, alongside C5a and IL-8.
- LTC4, LTD4, LTE4: bronchoconstriction, vasoconstriction, ↑ permeability. Together these are the "slow-reacting substance of anaphylaxis," blocked at the receptor by montelukast and zafirlukast.
Other mediators
Other mediators worth keeping straight
- Histamine from mast cells, basophils, and platelets: immediate vasodilation and permeability.
- Bradykinin from kininogen via kallikrein: pain and permeability, and the cause of ACE-inhibitor cough and angioedema.
- C3a and C5a, the anaphylatoxins; C5a is also chemotactic.
- Platelet-activating factor (PAF) and NO (vasodilation via cGMP).
Where each drug cuts
| Drug | Target | Blocks | Clinical consequence |
|---|---|---|---|
| Corticosteroids | Phospholipase A2 | Both prostaglandins and leukotrienes | Broadest anti-inflammatory effect |
| Aspirin | COX-1 and COX-2, irreversible | Prostaglandins, TXA2 | Antiplatelet for the platelet's lifespan |
| NSAIDs | COX-1 and COX-2, reversible | Prostaglandins, TXA2 | Analgesia, gastric ulcers |
| Celecoxib | COX-2 only | Inflammatory prostaglandins | Spares gastric mucosa, ↑ thrombotic risk |
| Zileuton | 5-lipoxygenase | All leukotrienes | Asthma |
| Montelukast | LTD4 receptor | LTC4/D4/E4 effects only | Asthma, especially aspirin-induced |
A woman with asthma and nasal polyps wheezes within an hour of taking aspirin. Why, and which drug class suits her asthma?
Blocking COX shunts arachidonic acid down the lipoxygenase arm, so more LTC4, LTD4 and LTE4 are made, causing bronchoconstriction. A leukotriene receptor antagonist such as montelukast fits aspirin-induced asthma.
How it's tested
Corticosteroids act higher in the cascade than NSAIDs: by inhibiting phospholipase A2 they block both prostaglandins and leukotrienes, whereas NSAIDs block only the COX arm. A stem that needs both arms suppressed is always steroids.
The second recurring question is aspirin-exacerbated respiratory disease: aspirin blocks COX, so arachidonic acid is shunted down the LOX arm → excess leukotrienes → bronchospasm, in the patient with nasal polyps and asthma. The treatment that fits the mechanism is a leukotriene modifier, not a stronger NSAID.
Go deeper
First Aid "Arachidonic acid products" diagram; Pathoma Ch. 2 "Chemical mediators"; SketchyPharm NSAIDs/leukotriene modifiers. Anchor the branch points (steroids = PLA2, NSAIDs = COX, zileuton = 5-LOX, montelukast = LTD4 receptor) and the TXA2 (aggregation) vs PGI2 (anti-aggregation) opposition.
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